Human immunodeficiency virus (HIV), which is also called human T-lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV)or AIDS-associated retrovirus (ARV), was first isolated in 1982 and has been identified as the etiologic agent of the acquired immunodeficiency syndrome (AIDS) and related diseases. Since then, chemotherapy of AIDS has been one of the most challenging scientific endeavors. So far, AZT, ddC, ddI, and D4T have been approved by FDA and are being clinically used as drugs for the treatment of AIDS and AIDS-related complex. Although these FDA-approved drugs can extend the life of AIDS patients and improve their quality of life, none of these drugs are capable of curing the disease. Bone-marrow toxicity and other side effects as well as the emergence of drug-resistant viral strains limit the long-term use of these agents..sup.1 On the other hand, the number of AIDS patients worldwide has increased dramatically within the past decade and estimates of the reported cases in the very near future also continue to rise dramatically. It is therefore apparent that there is a great need for other promising drugs having improved selectivity and activity to combat AIDS..sup.1 Several approaches including chemical synthesis, natural products screening, and biotechnology have been utilized to identify compounds targeting different stages of HIV replication for therapeutic intervention..sup.2 Very recently, the screening program at the National Cancer Institute has discovered a class of remarkably effective anti-FIIV natural products, named calanolides, from the rainforest tree Calophyllum lanigerum, with calanolide A, 1, being the most potent compound in the reported series..sup.3 For example, calanolide A demonstrated 100% protection against the cytopathic effects of HIV-1, one of two distinct types of HIV, down to a concentration of 0.1 .mu.M. This agent also halted HIV-1 replication in human T-lymphoblastic cells (CEM-SS) (EC.sub.50 =0.1 .mu.M/IC.sub.50 =20 .mu.M)..sup.3 More interestingly and importantly, calanolide A was found to be active against both the AZT-resistant G-9106 strain of HIV as well as the pyridinone-resistant A17 virus..sup.3 Thus, the calanolides, known as HIV-1 specific reverse transcriptase inhibitors, represent novel anti-HIV chemotherapeutic agents for drug development.
The only known natural source of calanolide A was destroyed and other members of the same species did not contain the desired material..sup.4 Consequently, a practical synthesis of the natural product must be developed for further study and development to be carried out on this active and promising series of compounds. Herein, we describe a method for the synthesis of (.+-.)-calanolide A and some related compounds. ##STR1##
The key intermediate in the inventive method of preparation is chromene 4, which is synthesized by the sequence depicted in Scheme I. Thus, 5,7-dihydroxy-4-propylcoumafin, 2,.sup.5 was prepared quantitatively from ethyl butyrylacetate and phloroglucinol under Pechman conditions..sup.6 Product yield and purity was dependent on the amount of sulfuric acid used. The 8-position of 5,7-dihydroxy-4-propylcoumafin, 2, was then selectively acylated at 8.degree.-10.degree. C. by propionyl chloride and A1Cl.sub.3 in a mixture of carbon disulfide and nitrobenzene to afford 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3. A route developed for synthesis of Mammea coumarins.sup.7 was initially attempted for preparation of compound 3, but it proved too awkward and low-yielding. The chromene ring was introduced upon treatment of compound 3 with 4,4-dimethoxy-2-methylbutan-2-ol,.sup.8 providing 4 in 78% yield. ##STR2##
As presented in Scheme II, Robinson-Kostanecki reaction.sup.9 on 4 by using sodium acetate in refluxing acetic anhydride produced enone 5 in a 65% yield. This intermediate failed to afford calanolide A upon reduction with borohydride reagents, presumably because attack at the pyrone and ring opening occurred preferentially. Treatment of 5 with Baker's yeast also resulted in coumarin ring cleavage while tri-n-butyltin hydride.sup.10 led to reduction of 5 to enol 6 in modest yield. Finally, (.+-.)-calanolide A was successfully formed with the desired stereochemical arrangement by treatment of 4 with acetaldehyde diethyl acetal in the presence of trifluoroacetic acid and pyridine with heating at 160.degree. C., followed by Luche reduction.sup.11 via chromanone 7 (see Scheme II). ##STR3##